The major research activity of the applicant is to direct the programs supported by the large program project grant, "Biological Aspect of Psychotic Disorders." The submitted research plan encompasses 150 pages and presents a very extensive and wide-ranging research program. The overall aims of this proposal are: (1) to maintain a research environment in which clinical and basic scientists can work together and develop joint hypotheses applicable to the understanding and treatment of psychotic disorders; (2) to continue to explore the mechanisms and dimensions of receptor adaptational phenomenon and the significance of this phenomenon in psychiatric disease and treatment; (3) to continue to investigate the role of prenatal influences on postnatal behavior and brain development; devise means for producing or preventing specific brain and/or behavioral effects; (4) to further explore the biochemistry of tissues accessible in the living human and devise appropriate methodology for the sound interpretation of biochemical data obtained with these tissues as a means for direct investigation of the pathology of humans with psychotic disorders. The major thrust of this proposal is to examine the way that neurotransmitters act on their target organs to maintain certain types of behaviors with a heavy consideration toward looking at the way in which these neurotransmitters modify receptors in the central nervous system. The author is particularly interested in the modification of dopamine receptor cells because these cells respond in a compensatory way to agonists or antagonists and can be regulated either by multiplying or diminishing in quantity so as to be supersensitive or subsensitive to applied or released transmitter substance. The idea of receptor sensitivity modification is central to this grant and in particular he is concerned with the modification of dopamine receptor sensitivity but at times considers norepinephrine as well as acetylcholine insofar as these are relevant to the aims of the grant. In addition, he has chosen to look at three diseases in regard to modification of receptor sensitivity and these include tardive dyskinesia, Tourettes' Syndrome and possibly Huntington's chorea and schizophrenia. The experiments proposed are many and include influences on the receptor ranging from drug and agonist induced influences through other neuronal inputs, environmental changes, as well as hereditary and disease processes that might change the sensitivity of the dopaminergic or other receptor cells in the central nervous system. The studies that he has proposed will use mice, rats and humans to examine receptor sites.